The specific aims of this proposal are (1) to characterize the daily rhythms of ciliary process cAMP and cGMP in vivo, and (2) to determine the roles of a2-adrenergic receptor control of adenylate cyclase, (3) natriuretic peptide control of cGMP, and (4) soluble guanylate cyclase, nitric oxide synthase modulation of cGMP in control of the circadian rhythms of intraocular pressure and the aqueous flow rate in rabbits and to explore the possible interaction between the sympathetic system and cGMP. Rabbits have robust, reproducible daily rhythms of intraocular pressure and aqueous flow, and the latter makes a significant contribution to the daily change of intraocular pressure. The PI observations of decreased nocturnal intraocular pressure, aqueous flow and the concentration of cyclic AMP in the aqueous after (-adrenergic blockade support a role for (-adrenergic receptor/adenylate cyclase mediated mechanisms in the nocturnal increases of intraocular pressure and aqueous flow. Sympathetic input via the ocular sympathetic nerves plays an important role in control of both rhythms; surgical sympathectomy markedly blunts the nocturnal increases of intraocular pressure, aqueous flow and aqueous cyclic AMP. In spite of ample evidence that a2-adrenergic agonists potently decrease intraocular pressure and the aqueous flow rate, a role for a2-adrenergic receptors in control of the rhythm of intraocular pressure remains to be demonstrated - While considerable evidence has been developed implicating cyclic AMP in control of intraocular pressure and aqueous flow, the role of cyclic GMP has been largely overshadowed by cyclic AMP until recently. While investigating the role a2-adrenergic receptors, the PI has developed a technique to measure endogenous iris-ciliary body and ciliary process cyclic nucleotides levels in vivo. Preliminary studies have demonstrated nocturnal increase of cAMP and cGMP in iris-ciliary processes suggesting that both cyclic nucleotides may play roles in control of the circadian rhythms of IOP and aqueous flow. Measurement of tissue cyclic nucleotide levels in vivo provides a powerful tool for elucidating their role in control of the circadian rhythms of aqueous flow and IOP.